Chiefs’ Inquiry Corner- 1/10/22

January 10, 2022

Chief residents of the NYU Langone Internal Medicine Residency give quick-and-easy, evidence-based answers to interesting questions posed by house staff, both in their clinics and on the wards.

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   Lithium therapy remains a cornerstone in the management of bipolar disorder, both for its efficacy in mood stabilization as well as in decreasing suicidality. However, long term use of lithium can have impacts on organs such as the kidneys and the thyroid, and serum levels must be monitored regularly to ensure they are within a relatively narrow therapeutic index (0.8-1.2 mmol/L during the acute manic phase of bipolar disorder, and 0.5-0.8 mmol/L for maintenance) to avoid toxicity. Lithium therapy is one of the most common causes of acquired nephrogenic diabetes insipidus (NDI), occurring in about 12% of people treated on lithium for 15 years (note that even in the absence of NDI, lithium therapy is commonly associated with polyuria or impaired renal concentrating ability of the urine, seen in 19% and 54% of people treated on lithium, respectively). A diagnosis of NDI is characterized by polydipsia, excessive urine production (>3L/day), and dilute urine (<300 mOsm/kg).   Lithium enters the principal cells of the collecting duct via epithelial sodium channels in the luminal membrane due to its chemical similarity to sodium. Its accumulation in the principal cells interferes with the ability of ADH to increase these cells’ water permeability through several mechanisms, including inducing molecular pathways that lead to lysosomal degradation of AQP2 water channels.  This NDI is usually at least partially reversible with discontinuation of the drug, although some studies suggest that eventually, with chronic lithium therapy (generally 15 years or longer), tubular damage may become permanent and drug discontinuation will not improve the NDI.  In many cases, however, discontinuation of the drug is not an option as the benefit of addressing the NDI does not outweigh the risk of poorly controlled psychiatric disease and its sequalae, including suicidality. In such cases, pharmacologic therapy can be attempted with amiloride, which inhibits the epithelial sodium channels in collecting tubule cells and can minimize further accumulation of lithium. Note that amiloride has limited efficacy in severe disease (urine Osm <200 mosmol/kg) and will not improve renal concentrating ability when permanent tubular damage is present.

References: Lithium and nephrotoxicity: a literature review of approaches to clinical management and risk stratification
  Aspergillus spores are ubiquitous in the environment (such as in soil and other vegetative material), and thus the pulmonary system is exposed to them daily. For the vast majority of people, inhalation of these spores does not lead to measurable colonization. For some, however, the acquisition and retention of Aspergillus can lead to a wide spectrum of clinical manifestations.  At one end of the spectrum is colonization of the pulmonary tree, often seen in people with histories of bronchiectasis, cystic fibrosis, and/or use of inhaled glucocorticoids. This is characterized by recurrent evidence of Aspergillus on culture, but without clinical symptoms or radiographic findings. Other clinical entities include tracheobronchitis (cough, wheezing, dyspnea, and hemoptysis, usually seen in people who have received lung transplants), chronic pulmonary aspergillosis (fever, cough, shortness of breath, and possibly chest pain and hemoptysis if angioinvasion is present, usually seen in people with structural lung disease, underlying cancer, malnutrition, critical illness, or chronic systemic glucocorticoids), and sinus disease (can resemble mucormycosis, with nasal congestion, fever, and facial pain, usually seen in people with neutropenia, diabetes, excessive EtOH use, and/or prolonged immunocompromised state). Aspergillosis can also present as a central nervous system infection as the result of hematogenous dissemination from a primary site or contiguous extension from a sinus infection, often seen in people on ibrutinib therapy. The most severe manifestation is invasive infection, marked by numerous small foci of growth of Aspergillus organisms leading to angioinvasion by vegetative hyphae with high risk of contiguous or hematogenous spread and subsequent fatal infection of multiple organ systems, including the heart (endocarditis). Risk factors for invasive Aspergillus infection include significant immunosuppression (such as in those receiving chemotherapy or who have received organ transplants) and severe respiratory viral infections, including influenza and SARS-CoV-2. 

References: Aspergillus Infections
It has been established that people living with HIV (PLWH) have higher rates (i.e., 4.5-fold) of sudden cardiac death (SCD) compared with the general population. PLWH have an increased risk of acute myocardial infarction, ischemic stroke, heart failure, pulmonary hypertension, and peripheral artery disease; the cause of this increased risk is multifactorial, involving HIV-specific mechanisms such as chronic immune activation and inflammation, dyslipidemia resulting from antiretroviral therapy, and behaviors such as smoking and alcohol use. These mechanisms underlie the increased risk for SCD, but it has thus far been unclear whether HIV infection itself is an independent risk factor. Data from the Veterans Aging Cohort Study recently aimed to assess whether HIV infection, CD4 cell counts, and/or HIV viral load were associated with risk of SCD. After adjusting for confounders such as coronary artery disease, heart failure, and smoking, a 14% higher risk for SCD in PLWH as compared to those without HIV was demonstrated. Risk factors for SCD in PLWH after adjusting for confounders included CD4 counts <200 cells/mm3 or viral load >500 copies/mL. In contrast, after adjusting for confounders, there was not an increased risk of SCD in PLWH who had CD4 counts >500 cells/mm3 or HIV viral load <500 copies/mL. This underscores the importance of reduction of both modifiable risk factors for SCD (such as diabetes and hyperlipidemia) as well as maintaining adherence to ART therapy, and thus the critical role for high-quality primary care, for people living with HIV.

References: HIV Infection and the Risk of World Health Organization-Defined Sudden Cardiac Death